Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) impose a substantial health burden, with nearly 200,000 cases and 75,000 deaths per year. Investigation of disease pathogenesis has focused largely on determinants of injury, however to date the focus on early events has not translated into clinically useful therapies. Using a mouse model of direct lung injury with intratracheal lipopolysaccharide (IT LPS), we identified lymphocyte influx into the alveolar compartment that correlated with resolution of injury. To test a potential role for lymphocytes in this process, we examined the response to IT LPS in lymphocyte-deficient Rag-1 null mice. Wild type (WT) and Rag-1 null mice exhibited similar injury patterns up to four days after LPS, however Rag-1 null mouse had profoundly impaired resolution, while WT mice completely recovered by day 10. In particular, inflammation persisted through day 10 in the Rag-1 null mice. Adoptive transfer of CD4+CD25+ regulatory T cells (Tregs) into Rag-1 null mice mediated resolution of injury, with clearance of inflammation and normalization of histologic changes. Preliminary studies indicate that Tregs likely mediate resolution of lung injury after bleomycin exposure as well, suggesting a general role for Tregs in resolution of lung injury. In vitro studies demonstrated that Tregs alter macrophage function, including altered cytokine expression profiles and phagocytosis, and enhance neutrophil apoptosis, consistent with facilitation of the transition from a pro-inflammatory microenvironment to one of recovery. We hypothesize that Tregs mediate resolution of acute lung injury by altering macrophage and neutrophil function in the alveolar compartment. We propose three aims to examine this hypothesis: 1) To examine the effectiveness of Tregs in mediating resolution of injury in distinct models of lung injury;2) To examine mechanisms by which Tregs mediate resolution of alveolar inflammation;and 3) To identify mechanisms intrinsic to Tregs that contribute to their function. We believe these studies will provide insights into resolution of lung injury, and will provide the impetus for identification of novel therapies to accelerate resolution in humans with ALI/ARDS. The focus on T regulatory cells or their products as mediators of resolution in lung injury is novel, and may provide new insights into a syndrome for which available therapies are extremely limited. PROJECT NARRATIVE. Acute lung injury is a potentially devastating clinical condition for which few therapies are available. We have identified an important role for a distinct subset of lymphocytes that are critical to achieve resolution of injury. These findings indicate new areas in which potential targets for therapy can be sought.